The proposal aims to develop new approaches to natural products discovery. While much effort has been placed on designing drug-like synthetic screening libraries, limited efforts have been put forth to logically design natural product screening libraries in terms of improving novelty of hits and increasing drug-like or lead-like structures within the library. This project will evaluate logical natural product library design on the outcome of high-throughput screening, primarily in the areas of oncology and infectious disease. In particular, we will apply LCMS-based untargeted metabolomics to help guide library design. We will use metabolomics, genomics, transcriptomics, and proteomics to investigate interspecies interactions. Understanding the systems biology governing interspecies interactions and secondary metabolite production will uncover new mechanisms to activate cryptic clusters. The outcomes of this proposal will be: (i) a template for producing natural product libraries enriched in new/novel small molecules with drug-like properties; and (ii) a platform for rapidly determining organisms where interspecies interactions change secondary metabolite production.